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De-epimerizing DyKAT of β-lactones generated by isothiourea-catalysed enantioselective [2 + 2] cycloaddition
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dc.contributor.author | Conboy, Aífe | |
dc.contributor.author | Goodfellow, Alister Stewart | |
dc.contributor.author | Kasten, Kevin | |
dc.contributor.author | Dunne, Joanne | |
dc.contributor.author | Cordes, David Bradford | |
dc.contributor.author | Buehl, Michael | |
dc.contributor.author | Smith, Andrew David | |
dc.date.accessioned | 2024-07-09T09:30:06Z | |
dc.date.available | 2024-07-09T09:30:06Z | |
dc.date.issued | 2024-04-24 | |
dc.identifier | 301262264 | |
dc.identifier | 923797ab-cb17-4364-8ebf-d93e37b45e12 | |
dc.identifier.citation | Conboy , A , Goodfellow , A S , Kasten , K , Dunne , J , Cordes , D B , Buehl , M & Smith , A D 2024 , ' De-epimerizing DyKAT of β-lactones generated by isothiourea-catalysed enantioselective [2 + 2] cycloaddition ' , Chemical Science , vol. 15 , no. 23 , pp. 8896-8904 . https://doi.org/10.1039/D4SC01410C | en |
dc.identifier.issn | 2041-6520 | |
dc.identifier.other | ORCID: /0000-0002-1095-7143/work/163571027 | |
dc.identifier.other | ORCID: /0000-0002-5366-9168/work/163571038 | |
dc.identifier.other | ORCID: /0000-0002-2104-7313/work/163571289 | |
dc.identifier.uri | https://hdl.handle.net/10023/30114 | |
dc.description | The research leading to these results has received funding from the EPSRC (KK, JD, EP/T023643/1) and the EaSI-CAT Centre for Doctoral Training (ASG). ADS thanks the EPSRC Programme Grant “Boron: Beyond the Reagent” (EP/W007517) for support. MB thanks EaStCHEM and the School of Chemistry for support. Computations were performed on a local HPC cluster maintained by Dr H. Früchtl. | en |
dc.description.abstract | An enantioselective isothiourea-catalysed [2 + 2] cycloaddition of C(1)-ammonium enolates with pyrazol-4,5-diones is used to construct spirocyclic β-lactones in good yields, excellent enantioselectivity (99 : 1 er) but with modest diastereocontrol (typically 70 : 30 dr). Upon ring-opening with morpholine or alternative nucleophilic amines and alcohols β-hydroxyamide and β-hydroxyester products are generated with enhanced diastereocontrol (up to >95 : 5 dr). Control experiments show that stereoconvergence is observed in the ring-opening of diastereoisomeric β-lactones, leading to a single product (>95 : 5 dr, >99 : 1 er). Mechanistic studies and DFT analysis indicate a substrate controlled Dynamic Kinetic Asymmetric Transformation (DyKAT) involving epimerisation at C(3) of the β-lactone under the reaction conditions, coupled with a hydrogen bond-assisted nucleophilic addition to the Si-face of the β-lactone and stereodetermining ring-opening. The scope and limitations of a one-pot protocol consisting of isothiourea-catalysed enantio-determining [2 + 2] cycloaddition followed by diastereo-determining ring-opening are subsequently developed. Variation within the anhydride ammonium enolate precursor, as well as N(1) and C(3) within the pyrazol-4,5-dione scaffold is demonstrated, giving a range of functionalised β-hydroxyamides with high diastereo- and enantiocontrol (>20 examples, up to >95 : 5 dr and >99 : 1 er) via this DyKAT. | |
dc.format.extent | 1272095 | |
dc.language.iso | eng | |
dc.relation.ispartof | Chemical Science | en |
dc.subject | DAS | en |
dc.title | De-epimerizing DyKAT of β-lactones generated by isothiourea-catalysed enantioselective [2 + 2] cycloaddition | en |
dc.type | Journal article | en |
dc.contributor.sponsor | EPSRC | en |
dc.contributor.sponsor | UK Research and Innovation | en |
dc.contributor.institution | University of St Andrews. School of Chemistry | en |
dc.contributor.institution | University of St Andrews. EaSTCHEM | en |
dc.identifier.doi | 10.1039/D4SC01410C | |
dc.description.status | Peer reviewed | en |
dc.identifier.grantnumber | EP/T023643/1 | en |
dc.identifier.grantnumber | EP/W007517/1 | en |
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